Multi-omics mechanistic investigation of Yograj Guggulu, an Ayurvedic polyherbal formulation, against MIA-induced osteoarthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Yograj Guggulu (YG) is a 29-ingredient Ayurvedic polyherbal formulation used for the management of degenerative joint disease (Sandhivata). It is described in the Bhaishajya Ratnavali and listed in the Ayurvedic Formulary of India. Despite continued use in Ayurvedic practice, its molecular mechanisms remain unexplored.

AIM OF THE STUDY: To evaluate the therapeutic effects of YG in experimental osteoarthritis (OA), identify bioavailable YG constituents, and trace their molecular targets within human OA disease networks.

MATERIALS AND

METHODS

Human OA disease networks were constructed from ten integrated synovial transcriptome datasets. YG was administered orally at three doses (135, 270, and 540 mg/kg) for 21 days to male Sprague-Dawley rats with mono-iodoacetate-induced knee OA (n = 8 per group). Functional recovery was assessed across five behavioral endpoints. Untargeted plasma metabolomics identified bioavailable YG metabolites. Knee-joint proteomics identified treatment-associated protein changes. Shortest-path analysis traced regulatory cascades from metabolite targets to attenuated proteins.

RESULTS

Low and medium YG doses restored pain sensitivity, locomotion, and gait toward normal levels. Qualitative gastric histology showed less mucosal injury than diclofenac sodium. Twenty-three bioavailable YG metabolites converged on four network-identified targets (NFKBIA, MMP9, PTGS2, FOS). Proteomics identified 364 disease-associated proteins that returned toward baseline abundance after treatment. Directed-network analysis connected the four targets to 45 of 70 attenuated proteins across NF-κB, IL-17, and extracellular matrix degradation cascades.

CONCLUSIONS

YG treatment is associated with attenuation of inflammatory and matrix-remodeling protein signatures in experimental OA. The four convergent targets provide a candidate mechanistic framework for its use in traditional Ayurvedic practice.